EP2564848A1 - Préparation contenant du donépézil absorbable par voie transdermique - Google Patents

Préparation contenant du donépézil absorbable par voie transdermique Download PDF

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Publication number
EP2564848A1
EP2564848A1 EP11775069A EP11775069A EP2564848A1 EP 2564848 A1 EP2564848 A1 EP 2564848A1 EP 11775069 A EP11775069 A EP 11775069A EP 11775069 A EP11775069 A EP 11775069A EP 2564848 A1 EP2564848 A1 EP 2564848A1
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Prior art keywords
donepezil
skin irritation
skin
mass
cholesterol
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EP11775069A
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German (de)
English (en)
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EP2564848A4 (fr
EP2564848B1 (fr
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Kazunosuke Aida
Yasunari Michinaka
Kenji Atarashi
Yasunori Takada
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Hisamitsu Pharmaceutical Co Inc
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Hisamitsu Pharmaceutical Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a transdermally absorbable donepezil-containing preparation with reduced skin irritation, a manufacturing method thereof, and a method for reducing skin irritation of a transdermally absorbable donepezil-containing preparation.
  • Donepezil is an acetylcholinesterase inhibitor, which is considered to be effective in drug treatment for Alzheimer's dementia.
  • donepezil preparations are only orally administered agents such as orally-disintegrating tablets and fine granules, containing donepezil hydrochloride.
  • metabolism/decomposition in liver cannot be avoided, and side effects in digestive system and transient and rapid increase in blood level may be observed.
  • the majority of patients with Alzheimer's dementia for whom therapeutic effects of donepezil are expected are elderly. Therefore, constant bioavailability is difficult to obtain by oral administration because of decreased digestive system function, and furthermore, there may also be problems of non-compliance.
  • the majority of patients with Down's syndrome and attention-deficit hyperactivity disorder, as well as Alzheimer's dementia, for which therapeutic effects of donepezil are expected are children. For this reason, the side effects of donepezil may become severe, and the problems of non-compliance may also arise like in the case of the elderly.
  • transdermally absorbable donepezil-containing preparation In order to reduce the above-mentioned problems and side effects by oral preparations, some transdermally absorbable donepezil-containing preparation have been recently proposed as alternatives to the oral preparations.
  • skin does not generally allow drugs to penetrate, it is difficult to allow a therapeutically effective amount of drug absorbed from the skin into the body, and thus there are also problems of sufficient skin permeability of drug for the transdermally absorbable donepezil-containing preparation.
  • Patent Literature 1 there are proposed transdermally-applied preparations containing, in addition to donepezil, a transdermal absorption enhancer selected from higher alcohols, lactic acid esters of higher alcohols, esters of higher fatty acids and lower alcohols, and esters of fatty acids having 6-18 carbon atoms and propylene glycol.
  • a transdermal preparation containing donepezil comprising Type-B crystal donepezil and/or salt thereof in an amount of 9-50% by mass relative to total weight of adhesive agent has excellent skin permeability.
  • Patent Literature 3 describes that cholesterol have no anti-inflammatory activity. Furthermore, it is described in Patent Literature 4 that cholesterol are effective in suppressing skin irritation of a tape-type transdermal preparation (plaster) containing bisphosphonate.
  • the object of an embodiment of the present invention is to provide a transdermal preparation containing one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, which has a low skin irritation as well as a sufficient skin permeability rate of donepezil.
  • transdermal preparation containing donepezil and a skin irritation-reducing agent has a low skin irritation as well as a sufficient skin permeability rate of donepezil, thereby having completed the present invention.
  • An embodiment of the present invention is to provide a transdermal preparation which comprises one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, and a skin irritation-reducing agent.
  • a transdermal preparation comprising one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, which has a drug skin permeability rate necessary for treatment, as well as a reduced skin irritation induced by the drug, when applied to the skin.
  • the skin irritation-reducing agent may be one or more cholesterol compounds selected from cholesterol, cholesterol derivatives and cholesterol analogs. Thereby higher skin permeability rate of donepezil can be achieved and skin irritation can be further reduced.
  • Content of the skin irritation-reducing agent may be 0.5-5% by mass relative to total amount of the transdermal preparation.
  • a transdermal preparation comprises one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, which has low skin irritation as well as a sufficient skin permeability rate of donepezil.
  • the present invention can also provide a manufacturing method of a transdermally absorbable donepezil-containing preparation with reduced skin irritation, and a method for reducing skin irritation of a transdermally absorbable donepezil-containing preparation.
  • An embodiment of the present invention provides a transdermal preparation which comprises, at least, one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, and a skin irritation-reducing agent.
  • Donepezil (IUPAC name: 2-[(1-benzyl-4-piperidinyl)methyl] -5,6-dimethoxyindane-1-on) is considered to increase the amount of brain acetylcholine and activate the brain cholinergic nervous system, by reversibly inhibiting acetylcholinesterase which is an acetylcholine-degrading enzyme.
  • Donepezil is a drug applied for inhibiting progress of Alzheimer's dementia. Drugs to be used may be free donepezil, or a pharmaceutically acceptable donepezil salt, or two or more combinations of them.
  • the pharmaceutically acceptable salts are not particularly limited and may be inorganic salts or organic salts.
  • the inorganic salts may include hydrochloride, bromate and silicate, and particularly hydrochloride is preferable.
  • the organic salts may include acetate, citrate, fumarate and maleate, and particularly acetate is preferable.
  • the content of the one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof may be a therapeutically effective amount, and although the content varies on the type of the transdermal preparation, generally the content may be 4-50% by mass, 5-30% by mass, furthermore 6-15% by mass relative to the total amount of the transdermal preparation.
  • total amount of the transdermal preparation herein means the total mass of the drug-containing part.
  • the total amount means the total mass
  • the dosage forms such as cataplasms, plasters and reservoir type patches, it means the mass of the part excluding the backing, and in the case of dosage forms such as sprays and aerosols, it means the mass of the part excluding the container part.
  • Epidermal cells play a central role in cutaneous immunity by releasing, to the outside of the cells, many proinflammatory substances such as cytokine, chemokine, inflammatory mediator and cell growth factor, and by expressing cytokine receptor, adhesion factor and MHC class II on the cells ("Handbook of Cutaneous Immunity" published by CHUGAI IGAKUSHA).
  • the proinflammatory substances released by epidermal cells include interleukin(IL)-1 ⁇ , IL-10, IL-12, IL-18, TNF- ⁇ , GM-CSF, IL-6, IL-7, IL-15, TGF- ⁇ , amphiregulin, HB-EGF, bFCTF, VEGF, PDGF, SCF, IFN- ⁇ , IFN- ⁇ , TGF- ⁇ , MIP-3 ⁇ , IP-9, IP-10, Mig, IL-8, GROa, RANTES, MCP-1, TARC, prostaglandin, leukotriene, substance P, reactive oxygen species and nitrogen oxide, and they cover a considerably broad range and intricately interact with each other to modulate immune reaction.
  • “reduction in skin irritation (reduced skin irritation)” herein means decreased production of a so-called skin irritation mediator induced by the drug, such as prostaglandin E2 (PGE2), IL-1 ⁇ , IL-6 and IL-8, in an in vitro test using epidermal cells, and/or reduction in skin irritation induced by the drug in vivo, such as skin erythema/crust and swelling formation.
  • the skin irritation may be evaluated by, for example, a skin primary irritation index (PII) as mentioned below.
  • a skin irritation-reducing agent there can be used, for example, aluminum hydroxide, titanium oxide, sucrose fatty acid ester, edetate, polyglyceryl fatty acid ester, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, and steroidal and non-steroidal anti-inflammatory agents.
  • sterol compounds such as cholesterol, cholesterol derivatives and cholesterol analogs are particularly preferable as the skin irritation-reducing agent for donepezil.
  • Cholesterol is a (3 ⁇ )-cholest-5-en-3-olcholest-5-en-3 ⁇ -ol and is known as essential component in a cell membrane of a higher animal.
  • the cholesterol derivative means a natural or synthetic cholesterol derivative and is exemplified by an acylcholesterol which is an ester compound in which a fatty acid binds to the part of the hydroxy group.
  • the cholesterol analog means a natural or synthetic cholesterol analog and is exemplified by plant cell-derived phytosterols such as sitosterol, stigmasterol, fucosterol, spinasterol, campesterol and brassicasterol, and a fungous-derived ergosterol, etc.
  • the transdermal preparation may comprise any one of or a combination of two or more of these sterol compounds. Since these sterol compounds have effects of reducing the skin irritation induced by donepezil, the skin irritation induced by donepezil can be reduced by adding these compounds.
  • the content of the skin irritation-reducing agent varies on the type of the transdermal preparation, and may be usually 0.1-30% by mass, 0.3-10% by mass, 0.5-5% by mass, and furthermore 0.5-3% by mass relative to the total amount of the transdermal preparation. In the case of 0.1% by mass or less, sufficient effects of reducing the skin irritation may not be obtained, and in the case of 30% by mass or more, sufficient adhesiveness of the transdermal preparation may not be obtained.
  • the transdermal preparation further comprises a transdermal absorption enhancer.
  • Transdermal absorption enhancers that can be used may be any of compounds in which the effects of promoting transdermal absorption in skins have been conventionally acknowledged.
  • promoting agents may be fatty acids having 6-20 carbon atoms, fatty alcohols, fatty acid esters, amides, ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters and ethers (these compounds may be saturated or unsaturated, and may be circular, linear or branched), lactic acid esters, acetic acid esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone derivatives, pirotiodecane, glycerine fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters (Span series), polysorbate-based compounds (Tween series), polyethylene glycol fatty acid esters, polyoxyethlene hydrogenated castor oil-based compounds (HCO series), poly
  • the examples can include caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetylalcohol, methyl laurate, hexyl laurate, lauric acid diethanol amide, isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, salicylic acid ethylene glycol, cinnamic acid, methyl cinnamate, cresol, cetyl lactate, lauryl lactate, ethyl acetate, propyl acetate, geraniol, thymol, eugenol,
  • oleyl alcohol, lauryl alcohol, isostearyl alcohol, lauric acid diethanol amide, glycerin monocaprylate, glycerin monocaprate, glycerin monooleate, sorbitan monolaurate, polyethylene glycol monolaurate, polyoxyethylene laurylether and pyrrothiodecane are particularly preferable.
  • a fatty acid having 6-20 carbon atoms is preferable, and oleic acid is particularly preferable.
  • Two or more kinds of such transdermal absorption enhancers may be mixed for use.
  • transdermal absorption enhancers By adding transdermal absorption enhancers it is possible to achieve sufficient skin permeability rate of donepezil.
  • the content of oleic acid usually may be 0.1-20% by mass, 0.5-15% by mass, 5-10% by mass, and furthermore 6-8% by mass relative to the total amount of the transdermal preparation.
  • a mass ratio of the drugs to the sterol compounds may be 20:1-1:10, 10:1-1:5, furthermore 5:1-1:1. These mass ratios make it possible to reduce skin irritation without affecting the skin permeability rate of donepezil.
  • a mass ratio of the drugs to oleic acid may be 1:10-5:1, 1:5-3:1, and furthermore 1:2-2:1. These mass ratios make it possible to achieve sufficient skin permeability rate of donepezil while suppressing skin irritation.
  • the dosage form of the transdermal preparation is not particularly limited, the form may be ointment, cream, gel, gelled cream, liniment and lotion, spray, aerosol, cataplasm, plaster, reservoir type patch, etc. Above all, in view of adherability and absorbability, plaster and ointment, which are dosage forms substantially free from moisture, are preferable. However, it is acceptable that the drug-containing composition has only 1% by mass or less of water (moisture) derived from its raw materials or manufacturing environment.
  • Plaster comprises a backing, and a drug layer laminated on at least one side of the backing.
  • the drug layer comprises one or more drugs selected from donepezil and its pharmaceutically acceptable salts, a skin irritation-reducing agent, and an adhesive base.
  • the skin irritation-reducing agent is preferably one or more sterol compounds selected from cholesterol, cholesterol derivatives and cholesterol analogs.
  • the drug layer may further contain a transdermal absorption enhancer like oleic acid.
  • the drug layer of the plaster is substantially free from moisture. “Substantially free from moisture” means that the drug layer is composed of non-aqueous materials. However, it is acceptable that the drug layer contains only 1% by mass or less of water (moisture) derived from its raw materials or manufacturing environment.
  • the adhesive base is exemplified by an acrylic adhesive base, a rubber adhesive base, and a silicone adhesive base, etc.
  • an acrylic adhesive base a single polymer or a copolymer of an alkyl (meth)acrylate ester having an alkyl group of 4-18 carbon atoms, or a copolymer of the above-mentioned alkyl (meth)acrylate ester and other functional monomer.
  • the (meth)acryl means acryl or methacryl.
  • an adhesive such as an acrylic acid/octyl acrylate ester copolymer, a 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution, an acrylic acid ester/vinyl acetate copolymer, a 2-ethylhexyl acrylate/2-ethylhexyl methacrylate/dodecyl methacrylate copolymer, a methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic polymer contained in acrylic resin alkanolamine solution, which are listed in Dictionary of Pharmaceutical Excipients, 2000 (edited by International Pharmaceutical Excipients Council Japan) as adhesives, DURO-TAK acrylic adhesive series (Henkel), Eudragit series (Evonik Industries) and the like.
  • the acrylic adhesive base is not particularly limited as long as it containing a copolymer comprising at least one of (meth)acrylic acid derivative represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2-ethylhexyl methacrylate and the like, and above all, a copolymer comprising 50% or more of 2-ethylhexyl acrylate is preferable.
  • the rubber adhesive base includes styrene-isoprene-styrene block copolymer (SIS), isoprene rubber, polyisobutylene (PIB), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), polysiloxane and the like, above all, SIS, PIB and polysiloxanes are preferable, and SIS and PIB are particularly preferable.
  • SIS styrene-isoprene-styrene block copolymer
  • PIB polyisobutylene
  • SBS styrene-butadiene-styrene block copolymer
  • SBR styrene-butadiene rubber
  • polysiloxane and the like above all, SIS, PIB and polysiloxanes are preferable, and SIS and PIB are particularly preferable
  • silicone adhesive base compounds having a main ingredient of a polyorganosiloxane or a polydimethylsiloxane are used.
  • Two or more of the above-mentioned adhesive bases may be mixed for use, and a content of the adhesive base may be usually 5-90% by mass, 10-70% by mass, and furthermore 10-50% by mass relative to the total amount, in consideration of formation of the drug layer and sufficient skin permeability rate of donepezil.
  • the drug layer may further contain a plasticizer.
  • the plasticizer is exemplified by petroleum-based oils such as paraffinic process oil, naphthenic process oil and aromatic process oil; squalane; squalene; vegetable oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil; silicone oil; dibasic acid esters such as dibutylphthalate and dioctylphthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate; diethylene glycol; polyethyleneglycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton and the like.
  • liquid paraffin liquid polybutene, isopropyl myristate, diethyl sebacate and hexyl laurate are preferable, and liquid polybutene, isopropyl myristate and liquid paraffin are particularly preferable.
  • Two or more of these plasticizers may be mixed for use.
  • a content of the plasticizer may be usually 10-70% by mass, 10-60% by mass, and furthermore 10-50% by mass relative to the total amount in consideration of sufficient skin permeability rate of donepezil and conservation of sufficient shear adhesion as a transdermal preparation.
  • the drug layer may contain a tackifying resin.
  • the tackifying resin includes a rosin, a glycerol ester of the rosin, a hydrogenated rosin, a rosin derivative such as a glycerol ester of the hydrogenated rosin and a pentaerythritol ester of the rosin, an alicyclic saturated hydrocarbon resin such as ARKON P100 (Trade name; Arakawa Chemical Industries, Ltd.), an aliphatic hydrocarbon resin such as QUINTONE B170 (Trade name; ZEON CORPORATION JAPAN), a terpene resin such as Clearon P-125 (Trade name; YASUHARA CHEMICAL CO.,LTD.), a maleic acid resin, etc.
  • the glycerol ester of the hydrogenated rosin, the alicyclic saturated hydrocarbon resin, the aliphatic hydrocarbon resin and the terpene resin are particularly preferable.
  • a content of the tackifying resin may be usually 5-70% by mass, 5-60% by mass, furthermore 10-50% by mass relative to the total amount, in consideration of sufficient adhesibility as a transdermal preparation and skin irritation while peeling off the transdermal preparation.
  • the backing is not particularly limited as long as it is suitable for backinging the drug layer, and stretch or non-stretch backing can be used.
  • Films or sheets of polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane and the like, and their laminated bodies, porous materials, foams, fabrics and non-woven fabrics, their laminated products and the like can be used.
  • side opposite to the side contacting the backing may be laminated with a release liner which is peeled off for use before being applied to an affected area.
  • a release liner polyethylene, polypropylene, polyester, polyethylene terephthalate, and their materials subjected to release treatment with silicone, and release sheet, etc. can be used.
  • a manufacturing method of the plaster will be explained.
  • a drug, oleic acid if needed, a sterol compound and an adhesive base are dissolved or dispersed in a solvent, and the resulting solution or dispersion liquid is either directly applied on the surface of a backing and dried to form a drug layer with a thickness of 30-200 ⁇ m, or the above-mentioned solution or dispersion liquid is firstly applied on a sheet or a film subjected to release treatment and dried to form an adhesive layer and thereafter the obtained adhesive layer is transferred to a backing by compression.
  • Solvent to be used in this manufacturing method is not particularly limited as long as it is an organic solvent compatible with all the blending components such as adhesive base and drugs, and as a solvent, for example, aromatic hydrocarbons such as toluene, benzene and xylene; esters such as ethyl acetate; halogenated hydrocarbons such as carbon tetrachloride, chloroform and methylene chloride can be used.
  • the transdermal preparation having the above-mentioned constructions can be manufactured by any of the traditionally known methods.
  • the adhesive base containing donepezil is melted by heating and is applied on a release sheet or a backing, then is stuck with a backing or a release sheet to obtain the preparation.
  • the preparation can be obtained by dissolving adhesive base component containing donepezil in a solvent such as toluene, hexane or ethyl acetate, and spreading the obtained liquid on a release sheet or a backing, drying to remove the solvents, and laminating with a backing or a release sheet.
  • the ointment contains one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, and a skin irritation-reducing agent.
  • a skin irritation-reducing agent one or more sterol compounds selected from cholesterol, cholesterol derivatives and cholesterol analogs are preferable.
  • a transdermal absorption enhancer such as oleic acid may be further contained.
  • the ointment is substantially free from moisture. “Substantially free from moisture” means that the ointment is made up of non-aqueous materials. However, it is acceptable that the ointment contains only 1% by mass or less of water (moisture) derived from its raw materials or manufacturing environment.
  • the ointment contains higher fatty acids such as myristic acid or their esters, waxes such as spermaceti, surfactants such as polyoxyethylene, hydrocarbons such as a hydrophilic Vaseline, in addition to the drug, oleic acid if needed, and a sterol compound.
  • higher fatty acids such as myristic acid or their esters, waxes such as spermaceti, surfactants such as polyoxyethylene, hydrocarbons such as a hydrophilic Vaseline, in addition to the drug, oleic acid if needed, and a sterol compound.
  • the ointment can be manufactured by adding 5-15% by mass of a higher fatty acid or its ester, 1-10% by mass of a surfactant, 0.1-30% by mass of the drug, 0.1-30% by mass of the sterol compound, 4-10% by mass of waxes and 50-90% by mass of hydrocarbons based on the total amount, heating them until the whole components in the solution become transparent, uniformly mixing them using a homo-mixer, and cooling them to the room temperature while stirring.
  • various pharmaceutically acceptable additives for example stabilizers, antioxidants, perfumes, fillers and transdermal absorption enhancers can be added within the ranges not impairing the object of the present invention.
  • another embodiment of the present invention provides a manufacturing method of the transdermally absorbable donepezil-containing preparation allowing reduction in skin irritation, and a method for reducing skin irritation of a transdermal preparation, which comprise a step of adding one or more drugs selected from donepezil and its pharmaceutically acceptable salts, and a skin irritation-reducing agent to the transdermal preparation.
  • Transdermally absorbable donepezil-containing preparations were prepared. Materials were mixed at the quantities as described in Table 1 to provide an application liquid. The application liquid was spread on a polyethylene terephthalate film subjected to release treatment, and solvent was removed the by drying with a hot air to provide a drug layer, on which a backing (Sand matte PET, Teijin Dupont Films Japan Limited) was laminated. Then, after being appropriately cut, transdermally absorbable donepezil-containing preparations in Examples 1-9 and Comparative Example 1 were obtained. It should be noted that the ratios in Table 1 are relative to the total amount (% by mass) of the transdermally absorbable donepezil-containing preparation.
  • the skin of a hairless mouse was peeled from side of the body, the transdermally absorbable donepezil-containing preparations (about 3 cm 2 ) in Example 6 and Comparative example 1 were applied to the horny layer side, and the skin was set on a flow-through cell, in which warm water (37°C) was circulated around the outer circumference, with the dermis side facing to the receptor side.
  • warm water 37°C
  • PBS phosphate buffered saline
  • sampling was carried out at a flow rate of about 5 mL/hr every 3 hours for the transdermal preparation in Example 6, or every 2 hours for the transdermal preparation in Comparative example 1, up to 24 hours.
  • LabCyte EPI-MODEL Japan Tissue Engineering Co., Ltd.
  • LabCyte is a cultured skin cultured in a transwell.
  • LabCyte was used with the transwell.
  • a cholesterol (Wako Pure Chemical Industries, Ltd.) was used as a test article. Donepezil hydrochloride was used as the drug. Olive oil (Wako Pure Chemical Industries, Ltd.) was used as a vehicle.
  • the test solutions of each group were added to the cells, the culture after being incubated for 48 hours were collected, and the production amounts of skin irritation mediators were measured.
  • PGE2, IL-1 ⁇ , IL-6 and IL-8 were measured as the skin irritation mediators.
  • the skin irritation mediators were measured by using a commercially available ELISA kit (R&D Systems, Inc.).
  • the relative production amount of the skin irritation mediator in the Cholesterol Addition Group was calculated as below, when the production amount of the skin irritation mediators in Drug Alone Group was set to 100.
  • Relative production amount production amount of the mediator in Cholesterol Addition Group / production amount of the mediator in Drug Alone Group ⁇ 100
  • the transdermally absorbable donepezil-containing preparations having a size of 2 cm x 2 cm in Examples 5-9 and Comparative example 1 were attached to a shaved dorsal skin of rabbit.
  • the preparation was peeled 24 hours after the attachment, the formation of skin erythema, crust and swelling were macroscopically observed 1 hour and 48 hours after peeling, and were scored based on the evaluation standard of Draize et al. shown in Table 3 and then the skin primary irritation index (PII) were calculated.
  • the results are shown in Fig. 2 .
  • the PII of transdermally absorbable donepezil-containing preparation with the addition of cholesterol was decreased, and when the content of cholesterol ranges 0.5-5% by mass, the PII of the preparation was sufficiently decreased in comparison with Comparative example 1 without cholesterol.
  • the transdermal preparation comprising one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, which has low skin irritation as well as a sufficient skin permeability rate of donepezil.
  • a manufacturing method of a transdermally absorbable donepezil-containing preparation with reduced skin irritation and a method for reducing skin irritation of a transdermal preparation which comprise a step of adding one or more drugs selected from donepezil and pharmaceutically acceptable salts thereof, and a skin irritation-reducing agent to the transdermal preparation.

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  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP11775069.5A 2010-04-28 2011-04-27 Préparation contenant du donépézil absorbable par voie transdermique Active EP2564848B1 (fr)

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JP2010104120 2010-04-28
PCT/JP2011/060298 WO2011136288A1 (fr) 2010-04-28 2011-04-27 Préparation contenant du donépézil absorbable par voie transdermique

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EP2564848A1 true EP2564848A1 (fr) 2013-03-06
EP2564848A4 EP2564848A4 (fr) 2013-11-06
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JP (1) JP5665861B2 (fr)
ES (1) ES2547888T3 (fr)
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WO (1) WO2011136288A1 (fr)

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TWI433904B (zh) * 2011-01-12 2014-04-11 Taiwan Biotech Co Ltd 多奈哌齊經皮貼片
WO2015072564A1 (fr) 2013-11-17 2015-05-21 株式会社メドレックス Agent transdermique en solution colloïdale
US11660344B2 (en) 2013-11-17 2023-05-30 Medrx Co., Ltd. Transdermal colloidal solution agent
JP6495339B2 (ja) * 2014-02-20 2019-04-03 エヌエーエル ファーマスーティカル グループ リミテッド ドネペジルを含む経皮薬物送達システム
US9987361B1 (en) 2014-12-29 2018-06-05 Noven Pharmaceuticals, Inc. Compositions and method for sustained drug delivery by active transdermal technology
WO2016190002A1 (fr) * 2015-05-26 2016-12-01 ニプロ株式会社 Timbre adhésif
CN109922796B (zh) 2016-06-23 2023-04-07 考里安有限责任公司 具有亲水和疏水域的粘合剂基质和治疗剂
US9993466B2 (en) 2016-07-27 2018-06-12 Corium International, Inc. Donepezil transdermal delivery system
WO2018022814A1 (fr) * 2016-07-27 2018-02-01 Corium International, Inc. Systèmes d'administration transdermique à pharmacocinétique bioéquivalent à l'administration orale
WO2018022818A1 (fr) 2016-07-27 2018-02-01 Corium International, Inc. Systèmes d'administration transdermique de mémantine
CA3086163A1 (fr) 2017-12-20 2019-06-27 Corium, Inc. Composition adhesive transdermique comprenant un agent therapeutique liquide volatil a bas point de fusion
KR102024996B1 (ko) * 2017-12-27 2019-09-25 동아에스티 주식회사 도네페질을 함유하는 치매 치료용 경피흡수제제
US20210290603A1 (en) * 2020-03-18 2021-09-23 Chemistryrx Methods for treating acne
WO2023240105A1 (fr) * 2022-06-07 2023-12-14 Biomimetix Jv, Llc Compositions hydrophobes contenant un principe actif hydrophile et méthodes associées

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See also references of WO2011136288A1 *

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Publication number Publication date
US20130053358A1 (en) 2013-02-28
ES2547888T3 (es) 2015-10-09
JPWO2011136288A1 (ja) 2013-07-22
EP2564848A4 (fr) 2013-11-06
JP5665861B2 (ja) 2015-02-04
TW201206505A (en) 2012-02-16
WO2011136288A1 (fr) 2011-11-03
TWI501790B (zh) 2015-10-01
EP2564848B1 (fr) 2015-09-02

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